LSTM Neural Network for Inferring Conduction Velocity Distribution in Demyelinating Neuropathies

Waveform analysis of compound muscle action potential (CMAP) is important in the detailed analysis of conduction velocities of each axon as seen in temporal dispersion. This understanding is limited because conduction velocity distribution cannot be easily available from a CMAP waveform. Given the recent advent of artificial intelligence, this study aimed to assess whether conduction velocity (CV) distribution can be inferred from CMAP by the use of deep learning algorithms. Simulated CMAP waveforms were constructed from a single motor unit potential and randomly created CV histograms (n = 12,000). After training the data with various recurrent neural networks (RNNs), CV inference was tested by the network. Among simple RNNs, long short-term memory (LSTM) and gated recurrent unit, the best accuracy and loss profiles, were shown by two-layer bidirectional LSTM, with training and validation accuracies of 0.954 and 0.975, respectively. Training with the use of a recurrent neural network can accurately infer conduction velocity distribution in a wide variety of simulated demyelinating neuropathies. Using deep learning techniques, CV distribution can be assessed in a non-invasive manner.

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA

Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology.Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.Results: Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

Facilitation of sensory axon conduction to motoneurons during cortical or sensory evoked primary afferent depolarization (PAD) in humans

Sensory and cortical pathways activate GABAergic interneurons with axo-axonic connections onto proprioceptive (Ia) afferents that depolarize these afferents (termed primary afferent depolarization, PAD). In rodents sensory-evoked PAD is produced by GABAA receptors at nodes of Ranvier in Ia-afferents, rather than at presynaptic terminals, and facilitates action potential propagation to motoneurons by preventing branch point failures, rather than causing presynaptic inhibition. Here we examined if PAD likewise facilitates the Ia-afferent mediated H-reflex in humans by evoking PAD with both sensory and corticospinal tract (CST) stimulation. H-reflexes in several lower limb muscles were facilitated by prior conditioning from low-threshold proprioceptive, cutaneous or CST pathways, with a similar time course (~200 ms) to the PAD measured in rodent Ia-afferents. Long trains of repeated cutaneous or proprioceptive afferent stimulation produced long-lasting facilitation of the H-reflex for up to 2 minutes, consistent with the tonic depolarization of rodent Ia-afferents mediated by nodal α5-GABAA receptors for similar stimulation trains. Facilitation of the conditioned H-reflexes was not mediated by direct facilitation of the motoneurons because isolated stimulation of sensory or CST pathways did not modulate the firing rate of tonically activated motor units in tested muscles. Furthermore, cutaneous conditioning increased the firing probability of a single motor unit during the H-reflex without increasing its firing rate at this time, indicating that the underlying excitatory postsynaptic potential (EPSP) was more probable, but not larger. These results are consistent with sensory and CST pathways activating nodal GABAA receptors that reduce intermittent failure of action potentials propagating into Ia-afferent branches.

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1–C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21–64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

Visual information increases the indirect corticospinal excitation via cervical interneurons in humans

Modulatory actions of inputs from the visual system to cervical interneurons (IN) for arm muscle control are poorly understood in humans. In the present study, we examined whether visual stimulation modulates the excitation of cervical IN systems mediating corticospinal tract (CST) inputs to biceps brachii (BB). Twenty-eight healthy volunteers were seated and electromyogram recordings from the BB were performed across six experiments, each with discrete objectives. A flash stimulator for visual stimulation (50-μs duration) was placed 60 cm from the participant's eye. The CST was stimulated with transcranial magnetic/electrical stimulation (TMS/TES, respectively) contralateral to the recording site. Visual stimulation with TMS/TES was randomly delivered during weak tonic BB contractions. Single TMS/TES-induced motor-evoked potentials (MEPs) were markedly enhanced from 60-100 ms after visual stimulation compared with the control condition. The MEPs were significantly increased by combining the electrical stimulation of the ulnar nerve at the wrist [7.5-12 ms of nerve stimulation (NERVE)/TMS interval] with and without visual stimulation compared to the algebraic summation of responses obtained with either TMS or NERVE. Interestingly, the combined stimulation -induced MEP facilitation was significantly increased after visual stimulation compared with the control. Single motor unit (MU) recording also revealed the further enhancement of combined stimulation effects on the firing probabilities of MU during visual stimulation, which was observed in the peaks of the peri-stimulus time histogram, 1-2 ms later than the onset latency. The present findings suggest that visual stimulation facilitates the oligosynaptic CST excitation of arm motoneurons mediated by the cervical IN system.

Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (p<0.05). Electrophysiological changes delineated children who were functionally stable from those who attained clinically significant gains in motor function.InterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

Fine-wire recordings of flexor hallucis brevis motor units up to maximal voluntary contraction reveal a flexible, nonrigid mechanism for force control

We recorded for the first time single motor unit action potential trains in the flexor hallucis brevis, a short toe muscle, over the full range of maximum voluntary contraction. Its motor units are recruited up to very high (98%) recruitment thresholds with a substantial range of discharge rates. We further show high variability with crossover of discharge rates as a function of recruitment threshold both between participants and between motor units within participants.

Modeling motor-evoked potentials from neural field simulations of transcranial magnetic stimulation

ObjectiveTo develop a population-based biophysical model of motor-evoked potentials (MEPs) following transcranial magnetic stimulation (TMS).MethodsWe combined an existing MEP model with population-based cortical modeling. Layer 2/3 excitatory and inhibitory neural populations, modeled with neural-field theory, are stimulated with TMS and feed layer 5 corticospinal neurons, which also couple directly but weakly to the TMS pulse. The layer 5 output controls mean motoneuron responses, which generate a series of single motor-unit action potentials that are summed to estimate a MEP.ResultsA MEP waveform was generated comparable to those observed experimentally. The model captured TMS phenomena including a sigmoidal input-output curve, common paired pulse effects (short interval intracortical inhibition, intracortical facilitation, long interval intracortical inhibition) including responses to pharmacological interventions, and a cortical silent period. Changes in MEP amplitude following theta burst paradigms were observed including variability in outcome direction.ConclusionsThe model reproduces effects seen in common TMS paradigms.SignificanceThe model allows population-based modeling of changes in cortical dynamics due to TMS protocols to be assessed in terms of changes in MEPs, thus allowing a clear comparison between population-based modeling predictions and typical experimental outcome measures.HighlightsA model of motor-evoked potential formation gives a realistic electromyogram in response to TMS.The model reproduces effects of SICI, ICF and LICI.A link between existing neural field modeling and realistic outcome measures of TMS is provided.